Combination andolast/glucocorticoids

ABSTRACT

The invention relates to the combination of Andolast, a calcium-activated potassium channel opener and glucocorticoids for the treatment of patients suffering for airway diseases. Pharmaceutical compositions comprising Andoalst and glucocorticoids are also disclosed.

FIELD OF THE INVENTION

The present invention relates to the combination of andolast andglucocorticoids for the treatment of patients suffering from asthma,COPD or other respiratory diseases.

BACKGROUND OF THE INVENTION

Asthma is a chronic inflammatory disease of the respiratory system inwhich the airways narrow in response to different stimuli such asexposure to allergens, cold air, exercise and others. This narrowingcauses symptoms such as wheezing, breathlessness, chest tightness andcoughing, particularly at night or in the early morning.

Medication for asthma are used to reverse and prevent symptoms andairflow limitation and include controllers (or preventers) andrelievers. The goal of treatment is to achieve “asthma control”, whichmeans to minimize day- and night-time symptoms, activity limitation,airway narrowing and rescue bronchodilator use, and therefore reduce therisk of life-threatening exacerbations and long term morbidity.

Controllers are medications taken daily on a long-term basis that areuseful in getting and keeping persistent asthma under control.Controllers include inhaled glucocorticoids, leukotriene modifiers, mastcell stabilizers, anticholinergics and long-acting β₂-agonists.

Relievers include short-acting, selective β₂-adrenoreceptor agonists,such as salbutamol and terbutaline, that act to relievebronchoconstriction and its accompanying acute symptoms.

Chronic Obstructive Pulmonary Disease (COPD) is a disease statecharacterized by airflow limitation that is not fully reversible. Theairflow limitation is usually both progressive and associated with anabnormal inflammatory response of the lungs to noxious particles, mostoften related to cigarette smoking.

The chronic airflow limitation characteristic of COPD is caused by amixture of small airway disease (obstructive bronchiolitis) andparenchymal destruction (emphysema).

Chronic inflammation causes remodelling and narrowing of the smallairways. Destruction of the lung parenchyma, also by inflammatoryprocesses, leads to the loss of alveolar attachments to the smallairways and decreases lung elastic recoil; in turn, these changesdiminish the ability of the airways to remain open during expiration.The terms “emphysema” and “chronic bronchitis” are frequently usedclinically and included in the definition of COPD. Emphysema, ordestruction of the gas-exchanging surfaces of the lung (alveoli),describes one of several structural abnormalities present in patientswith COPD.

As anticipated above, COPD is delineated by chronic inflammationthroughout the airways, parenchyma, and pulmonary vasculature. Theintensity as well as the cellular and molecular characteristics of theinflammation vary as the disease progresses. Over time, inflammationdamages the lungs and leads to the pathologic changes characteristic ofCOPD (Sutherland et al.; N. Engl. J. Med. 2004 (350), 2689-97). In fact,COPD is characterised by an increase in neutrophils, macrophages, and Tlymphocytes in various parts of the lungs. There may also be an increaseof eosinophils in some patients, particularly during exacerbations.

Pharmacological therapy is used to prevent and control symptoms, reducethe frequency and severity of exacerbations, improve health status, andimprove exercise tolerance. Therefore, treatment of COPD heavily dependson anti-inflammatory and bronchodilator drugs. However, none of theexisting medications for COPD have been shown to modify the long-termdecline in lung function that is the hallmark of this disease.

Andolast (CR 2039), chemically defined asN-4-(5-tetrazolyl)-phenyl-4-(5-tetrazolyl)-benzamide is a novelantiallergic and anti-inflammatory agent, belonging to a new class ofcalcium-activated potassium (K⁺) channel openers.

Different sets of experiments have shown that Andolast relieves thedifferent components of the airways inflammatory response. The compounddecreases both the antibody-mediated and the cell-mediated inflammatoryresponses in atopic subjects. With regard to the former, Andolast has apotent inhibitory effect on IL-4 dependent IgE synthesis by human Blymphocytes from allergic donors: this effect leads to the decrease inallergen-triggered mast cells sensitisation and consequently to theinhibition of IgE-dependent mediator release.

With respect to cell-mediated processes, preliminary in-vivo data fromatopic asthmatic patients indicated that Andolast induces an inhibitoryeffect on T lymphocytes (Th₂) production of the eosinophil recruitercytokine IL-5.

The currently clinical pharmacology evidence indicates that Andolastadministered by inhalation at doses ranging from 2 to 20 mg prevents ina dose-dependent fashion the airway hyperresponsiveness to specific aswell as to non-specific bronchostimulation challenges such as AMP,exercise, UNDW (ultrasonically nebulized distilled water) and CAH(cold-dry air hyperventilation) in mild-moderate asthmatic patients.Moreover, Andolast completely prevents the early as well as the lateairway response following specific antigen challenge.

DETAILED DESCRIPTION OF THE INVENTION

As specified above, the instant invention relates to a novel drugcombination of andolast and glucocorticoids for the treatments ofpatients suffering from asthma, COPD or other respiratory diseases.

Andolast (CR 2039) chemically defined asN-4-(5-tetrazolyl)-phenyl-4-(5-tetrazolyl)-benzamide, has been mentionedin WO90/09989 as a potential agent for treatment of various conditionswhich can be attributed to hypersensitivity to allergens, such asbronchial asthma, allergic rhinitis and conjunctivitis and in EP1634595as a drug to be used for the treatment of COPD.

Furthermore, suitable pharmaceutical formulations for the use ofAndolast in the treatment of asthma have been described in U.S. Pat. No.5,976,576.

Andolast is preferably used as di-sodium salt (and/or as solvatethereof).

Preferably, Andolast and the glucocorticoids are administered byinhalation at therapeutically effective dosages which, when combined,provide a rapid and sustained benefical effect for treating asthma, COPDand other airway disorders.

Definitions

Andolast can form salts and solvates which are also within the scope ofthis invention. Reference to Andolast is understood to include alsosalts and solvates thereof, unless otherwise indicated.

Glucocorticoids are a sub-class of corticosteroids, hormones that areproduced in the adrenal cortex and are involved in a wide range ofphysiologic actions such as control of carbohydrate, fat and proteinmetabolism and are anti-inflammatory by preventing phospholipid release,decreasing eosinophil action and other mechanisms.

Synthetic glucocorticoids are used in the treatment of joint pain,dermatitis, hepatitis, lupus erythematosus, allergic reactions, asthmaand other diseases for glucocorticoid replacement.

The preferred pharmacologically active glucocorticoids agents for use inaccordance with the present invention include but are not limited tobeclometasone dipropionate, fluticasone propionate, budesonide,mometasone furoate, zoticasone, dexamethasone and ciclesonide.

The term “combination” applied to active ingredients is used herein todefine a single pharmaceutical composition (formulation) comprising bothdrugs of the invention (i.e., Andolast and glucocorticoid) or twoseparate pharmaceutical compositions (formulations), each comprising asingle drug of the invention (i.e., Andolast or a glucocorticoid), to beadministered conjointly.

Within the meaning of the present invention, the term “conjointadministration” is used to refer to administration of Andolast and aglucocorticoid simultaneously in one composition, or simultaneously indifferent composition, or sequentially.

For the sequential administration to be considered “conjoint”, howeverAndolast and the glucocorticoid must be administered separately by atime interval that still permits to obtain rapid onset of action as wellas good long-term efficacy for the treatment of asthma, COPD and otherrespiratory diseases. For example, Andolast and the glucocorticoid mustbe administered on the same day (e.g., each—once or twice daily),preferably within an hour of each other, and most preferablysimultaneously.

The term “treating” is used herein to mean to relieve, alleviate, delayor prevent at least one symptom of disease in a subject. For example, inrelation to patients with allergic asthma, the term “treat” may mean toimprove quality of life of patients, associated with less exacerbationsand greater reductions in the use of inhaled glucocorticoids.

As used herein the term “therapeutically effective” applied to dose oramount refers to that quantity of a compound or pharmaceuticalcomposition that is sufficient to result in a desired activity uponadministration to a human subject in need thereof. More specifically,the term “therapeutically effective” refers to that quantity of acompound or pharmaceutical composition that is sufficient to reduce oreliminate at least one symptom of asthma, COPD and other airwaydisorders.

The phrase “pharmaceutically acceptable”, as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not produce untoward reactions when administered to humans.Preferably, as used herein, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in humans.

Within the meaning of the present invention, use is understood asmeaning the oral inhalation, preferably administered in the form of anaerosol, the aerosol having a particle diameter preferably of between0.1 and 10 microns and an average diameter preferably of between 1 and 3microns.

Aerosol generation cab be performed by pressure jet atomizers, bypropellant metered aerosols or by means of propellant-free conventionalportable inhalers for dry powders as for example MIAT Monohaler®,Diskhaler®, Turbohaler® and Rotadisk®.

The administration forms, depending of the inhalation system used, maycomprise the required excipients. In the case of powder inhalerswater-soluble carriers, preferably lactose, sweeteners, preferablysodium saccharin, flavouring, preferably menthol or peppermint oil; inthe case of metered aerosols propellants, emulsifiers, stabilizers,preservatives.

Andolast, preferably as di-sodium salt, is usually administered in adose-range from 2 to 24 mg, advantageously from 8 to 16 mg, from one tothree times daily.

The glucocorticoid, depending on the active compound, is usuallyadministered in a dosage of 0.05 to 2 mg per day. In the case of thebudenoside the daily preferred dosage may be in the range of from 0.1 to1 mg daily.

The invention further provides pharmaceutical preparations for treatingasthma, COPD and other airway disorders, which preparations comprise asactive compounds, Andolast and a glucocorticoid.

The invention also provides a pharmaceutical medicament comprising oneor more containers containing one or more of the ingredients of theformulations of the invention. In a related embodiment, the presentinvention provides a kit for the preparation of the pharmaceuticalcompositions of the invention, said kit comprising Andolast in a firstcontainer, and a glucocorticoid in a second container, and, optionally,instructions for admixing the two drugs and/or for administration of thecompositions. Each container of the kit may also optionally include oneor more physiologically acceptable carriers and/or excipients and/orauxiliary substances. Associated with such container(s) can be a noticein the form prescribed by governmental agency regulating themanufacture, use or sale pharmaceuticals products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration.

According to the methods of the present invention, the pharmaceuticalcompositions described herein are administered to patient attherapeutically effective doses, preferably, with minimal toxicity.Preferably, Andoalst and the glucocorticoid are each used at a dosagewhich, when combined, provide an enhanced effect, most preferably, aneffect not observed upon administration of each agent alone.

The invention is illustrated further by the following specificpharmaceutical compositions which should not, however, be considered inany way limiting of the invention.

EXAMPLE 1

Andolast sodium salt 8.00 mg Budesonide 0.20 mg Lactose 7.00 mg Menthol0.30 mg Sodium Saccharin 0.50 mg Total 16.00 mg

EXAMPLE 2

Andolast sodium salt 16.00 mg Budesonide 0.20 mg Lactose 6.80 mg Menthol0.40 mg Sodium Saccharin 0.60 mg Total 24.00 mg

EXAMPLE 3

Andolast sodium salt 8.00 mg Fluticasone propionate 0.25 mg Lactose 7.00mg Menthol 0.30 mg Sodium Saccharin 0.45 mg Total 16.00 mg

EXAMPLE 4

Andolast sodium salt 8.00 mg Beclometasone dipropionate 0.25 mg Lactose7.00 mg Menthol 0.30 mg Sodium Saccharin 0.45 mg Total 16.00 mg

The efficacy of Andolast, glucocorticoids and their combinations wasdetermined in preclinical studies using small animal models (e.g., rats)in which both the components of the invention have been found to betherapeutically effective.

The drug combination of the invention is not only highly effective atrelatively low doses, but also posses low toxicity and produces few sideeffects.

Preclinical Studies

The combination treatment of Andolast with prednisolone, taken as therepresentative of glucocorticoids, has been studied in comparison withthe monotherapy of the same drugs in one model of lung eosinophilia andhyperreactivity in rats, mimicking conditions of human asthma.

Effect on Sephadex-induced Eosinophilia and Lung Hyperresponsiveness inRats

Lung eosinophilia and hyperreactivity are characteristic of chronicasthma. Eosinophilia and hypereactivity in the lungs of rats was inducedby intravenous injection of Sephadex particles, according to the methodof Spicer et al. (Brit. J. Pharmacol. (1990), 101, 821-828). A singleinjection of Sephadex G100 induces an increase in number of eosinophilsin the bronchoalveolar lavage (BAL) fluids of the rats and moreover theanimals become hyperresponsive to the bronchoconstriction induced byacethylcholine (Ach).

In this context, we examined the effect of Andolast, prednisolone andone combination of these two drugs.

On day 0 the animals were injected i.v. (5 ml/kg) with 1.5 mg/mlsuspension of Sephadex G100.

The same day rats received the drugs 1 hour before and 3 hours after theinjection of G100. The drug treatment was followed once a day from day 1to day 3 and 1 hour before measurement of airway responsiveness to Achon day 4.

Andolast di-sodium salt was given i.m. 3 ml/kg dissolved in saline,prednisolone was given orally 5 ml/kg suspended in 0.5% methylcellulose.Bronchoconstriction was induced by Ach; it was administered i.v. (1ml/kg) at 5 min intervals and was increased from 0.03, 0.1, 0.3 to 3mg/kg.

Bronchoconstriction was determined as ED₅₀ (mg/kg), i.e. the dose of Achwhich produced 50% response calculated from the regression line of thedose-response curve. The results obtained are shown in Table 1.

TABLE 1 Protective effect of Andolast, prednisolone and theircombination treatment on airway hyperresponsiveness induced by SephadexG100 particles. Ach Treatment Doses ED₅₀ Protective⁽¹⁾ group (mg/kg)(mg/kg) Effect (%) Control (C) — 0.32 — G-100 (G) — 0.14 — G-100 (T)Andolast (3) 0.20 33.3 G-100 (T) Prednisolone (1) 0.16 11.1 G-100 (T)Prednisolone (10) 0.30 88.8 G-100 (T) Andolast (3) + Prednisolone (1)0.28 77.7 ⁽¹⁾The protective effect (%) was calculate by the formula:$\frac{\left( {T - G} \right)}{\left( {C - G} \right)} \times 100$

The calculated protective effects of Andolast (3 mg/kg) and prednisolone(1 mg/kg) given alone were 33.3% and 11.1%, respectively, whereas theprednisolone (10 mg/kg) produced an almost complete protection (88.8%).The combination treatment at the given doses produced a 77.7%protection.

Therefore the combination treatment produced a synergistic increase inefficacy for both drugs, as for example Andolast (3 mg/kg) was able toproduce an increase of efficacy of prednisolone (1 mg/kg) of about 7times.

The counts of eosinophils in the BAL fluid were significantly increasedin the Sephadex-injected (control) rats (2.6×10⁶) as compared to thosein the normal rats (about 1×10⁴).

Prednisolone (10 mg/kg) totally suppressed the eosinophilia in the BALfluids, whereas prednisolone (1 mg/kg) was poorly effective (2×10⁶).

Andolast (3 mg/kg) slightly inhibited lung eosinophilia (1.75×10⁶),whereas the combination treatment produced about a 80% protection(0.52×10⁶).

Therefore also in the case of eosinophilia in the BAL fluids thecombination treatment produced a synergistic protective effect for bothdrugs.

Clinical Studies

Safety and Efficacy of Andolast as Add-on to Glucocorticoids in theRelief of Allergic Asthma

To assess the safety and efficacy of Andolast in adult patients withpersistent asthma treated with glucocorticoids, we propose to conduct amulticenter, randomized, placebo-controlled, double-blind,dose-response, parallel-group trial of inhaled Andolast as add-ontreatment to low-dose of inhaled budesonide to investigate the efficacyand safety of this drug combination.

The synopsis below describes a possible study design.

Only patients with mild to moderate persistent allergic asthma (FEV₁≦80%of predicted value) will be enrolled in this study.

To participate patients must have received during a run-in period of 4weeks an adequate dose of metered-dose inhaled glucocorticoid(budesonide 400 mcg b.i.d.) to reach an adequate asthma control.

Eligible patients, i.e. patients that have obtained asthma control asshown by a significant improvement in FEV₁ and symptoms, will berandomised, stratified according to asthma severity in four groups oftreatment, as follows:

-   -   Placebo (budesonide 100 mcg b.i.d.)    -   Andolast (budesonide 100 mcg+Andolast 8 mg b.i.d.)    -   Andolast (budesonide 100 mcg+Andolast 16 mg b.i.d.)    -   Andolast (budesonide 100 mcg+Andolast 24 mg b.i.d.)

Patients will record lung function and day time and nigh time asthmasymptoms throughout the study.

The primary objective of the study is to assess the effect of treatmenton airway obstruction (FEV₁, PEF and FVC), “rescue” medication use, dayand night-time asthma symptoms score, activity limitation, number ofexacerbations, time to first exacerbation of asthma, drop-out to severeasthma exacerbation.

While the invention has been depicted and described with reference toexemplary embodiments, such reference does not imply a limitation on theinvention, and no such limitation is to be inferred. The invention iscapable of considerable modification, alteration, and equivalents inform and function, as will be apparent to those of ordinary skill in thepertinent art having the benefit of this disclosure. Consequently, theinvention is intended to be limited only by the spirit and scope of theappended claims, giving full cognizance to equivalence in all respects.

The invention claimed is:
 1. A method of treating asthma, COPD, or arespiratory disease comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of (i) Andolastdi-sodium salt and/or a solvate thereof and (ii) a secondtherapeutically effective amount of budesonide, wherein Andolastdi-sodium salt and/or solvate thereof and budesonide are in a ratio byweight of between 8 and 320 with reference to the Andolast di-sodiumsalt.
 2. The method of claim 1 in which the respiratory disease isselected from the group consisting of bronchitis, obstructivebronchitis, allergic bronchitis, pulmonary fibrosis, pneumonia,emphysema.
 3. The method of claim 1 in which andolast di-sodium salt andbudesonide are administered conjointly.
 4. The method of claim 1 inwhich andolast di-sodium salt and budesonide are administeredsequentially.
 5. The method of claim 1 in which andolast di-sodium saltand budesonide are administered simultaneously, sequentially orseparately by oral inhalation.
 6. The method of claim 1 in whichandolast di-sodium salt is used as add-on to budesonide in long-termmaintenance treatment of asthma, COPD and other respiratory diseases.